Received: 15 December 2020
`
`Revised: 2 June 2021
`
`Accepted: 7 June 2021
`
`DOI: 10.1002/jha2.252
`
`REVIEW ARTICLE
`
`
`
`British Society for
`Haematology
`
`® Checkfor updates
`
`The beginning of a new therapeutic era in acute myeloid
`leukemia
`
`Christian Récher ©
`
`Service d’Hématologie, Centre Hospitalier
`Universitaire de Toulouse,Institut
`Universitaire du Cancer de Toulouse
`Oncopole, Université ToulouseIII Paul
`Sabatier, Centre de Recherches en
`Cancérologie de Toulouse, Toulouse, France
`
`Correspondence
`Christian Récher, Service d’Hématologie,
`Centre Hospitalier Universitaire de Toulouse,
`Institut Universitaire du Cancer de Toulouse
`Oncopole, Université ToulouseII Paul Sabatier,
`Centre de Recherches en Cancérologie de
`Toulouse, Toulouse, France.
`Email: recher.christian@iuct-oncopole.fr
`
`Abstract
`
`In the field of AML, the early 2000s were shaped by the advent of novel molecular
`
`biology technologies including high-throughput sequencing that improved prognostic
`
`classification, response evaluation through the quantification of minimal residual dis-
`
`ease, and the launchof research on targeted therapies. Our knowledge of leukemoge-
`
`nesis, AML genetic diversity, gene-gene interactions, clonal evolution, and treatment
`
`response assessmenthasalso greatly improved. Newclassifications based on chromo-
`
`somal abnormalities and gene mutations are now integrated on a routine basis. These
`
`considerable efforts contributed to the discovery and developmentof promising drugs
`
`whichspecifically target gene mutations, apoptotic pathways andcell surface antigens
`
`as well as reformulate classical cytotoxic agents. In less than 2 years, nine novels drugs
`
`have been approved for the treatment of AML patients, and many others are being
`
`intensively investigated,in particular immune therapies. There are now numerous clini-
`
`calresearch opportunities offered to clinicians, thanks to these new treatment options.
`
`Weareonly at the start of anew era which should see major disruptions in the way we
`
`understand, treat, and monitor patients with AML.
`
`KEYWORDS
`
`acute myeloid leukemia, CPX-351, enasidenib, FLT3 inhibitors, gemtuzumab ozogamycin,gilter-
`itinib, glasdegib, IDH inhibitors, ivosidenib, midostaurin, monoclonal antibodies, oral azacitidine,
`TP53, venetoclax
`
`1
`
`|
`
`INTRODUCTION
`
`It has long been written that there was no breakthrough for the
`treatment of acute myeloid leukemia (AML) as compared to other
`hematological malignancies including chronic myeloid leukemia, B-cell
`lymphoma (BCL), or multiple myeloma [1]. Going back more than
`20 years ago, the situation was roughly similar for multiple myeloma.
`Youngerpatients were treated with high-dose melphalan and autolo-
`gous stem-cell transplantation while older patients received low-dose
`melphalan and prednisone, the so-called MP regimen that has fallen
`
`into oblivion over the years [2]. Now, there have been more than 10
`novel drugs approved in myelomatargeting intracellular pathways,
`tumor microenvironment, and cell surface antigens the combinations
`of which have transformed a highly deadly disease into a chronic
`one[3, 4]. In AML, we have beenrelying for the past 40 years on the
`combination of cytarabine and an anthracycline, so-called (“7+3”), as
`induction chemotherapy in patients suitable for intensive treatments
`followed by high-dose cytarabine consolidation and eventually by
`allogeneic stem cell transplantation (cure being the goal), whereas
`older or unfit patients received low-dose cytarabine or more recently
`
`This is an open accessarticle under the terms of the Creative CommonsAttribution License, which permits use, distribution and reproduction in any medium, provided
`the original work is properly cited.
`© 2021 The Authors. eJHaem published by British Society for Haematology and John Wiley & SonsLtd.
`
`eJHaem. 2021;2:823-833.
`wileyonlinelibrary.com/journal/jha2
`823
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`CELGENE 2110
`APOTEX v. CELGENE
`IPR2023-00512
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`

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`4| WILEY
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`RECHER
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`TABLE1=Novel drugs recently approvedin acute myeloid leukemia
`
`Agent
`
`Midostaurin
`
`Enasidenib
`
`CPX-351
`
`Approval
`
`2017
`
`Mechanismofaction
`
`FLT3inhibition
`
`2017
`
`2017
`
`IDH2 mutantinhibition
`
`Liposomal formulation
`including daunorubicin
`and cytarabineat a fixed
`5-molar:1-molar ratio
`
`CD33 monoclonal antibody
`linked to calicheamicin
`
`IDH1 mutantinhibition
`
`Hedgehog pathway
`inhibition
`
`Bcl-2 inhibition
`
`FLT3inhibition
`
`Hypomethylating agent
`
`Indication
`
`Newly diagnosed AML with FLT3 mutation
`in combination with standard induction,
`consolidation +/-maintenance
`
`Relapsed or refractory AML with IDH2
`mutation
`
`Newly diagnosed, therapy-related AML
`(t-AML) or AML with
`myelodysplasia-related
`
`Newly diagnosed, CD33-positive AML in
`combination with standard induction and
`relapsed or refractory CD33-positive
`AML
`
`Relapsed or refractory or newly diagnosed
`(unfit) AML with IDH1 mutation
`
`Unfit or older (>75y) patients with newly
`diagnosed AML in combination with
`low-dose cytarabine
`
`Unfit or older (>75y) patients with newly
`diagnosed AML in combination with
`hypomethylating agents or low-dose
`cytarabine
`
`Relapsed or refractory AML with FLT3
`mutation
`
`Continued treatment of AML patients who
`achieved CR/CRifollowing intensive
`induction chemotherapyand are not able
`to complete intensive curative therapy
`(i.e., alloSCT)
`
`changes (AML-MRC)
`
`Gemtuzumab ozogamicin
`
`2017
`
`lvosidenib
`
`Glasdegib
`
`Venetoclax
`
`Gilteritinib
`
`Oral azacitidine
`
`2018
`
`2018
`
`2018
`
`2018
`
`2020
`
`hypomethylating agents, both inducing few complete responses (CRs)
`andlittle hope for cure (prolonged survival being the goal) [5]. Then,
`genomics changed the game.Firstly, targeted gene sequencing succes-
`sively identified FLT3-ITD, CEBPA, and NPM1 mutations which helped
`improve prognostic classification, the response evaluation through
`quantification of molecular residual disease, and launched the research
`on targeted therapies leading to the registration of midostaurin as the
`first FLT3 inhibitor in AML [6, 7]. Soon after, thanks to the advance
`in high-throughput sequencing technologies, the first AML genome
`was reported in 2008 and subsequent studies identified several
`novel recurrent mutations with pathophysiological, prognostic, or
`therapeutic relevance such as |DH1, IDH2, or TP53 mutations [8-10].
`Our knowledge of leukemogenesis, AML genetic diversity, gene-gene
`interactions, clonal evolution, and treatment response assessmenthas
`also greatly improved, and new classifications based on chromosomal
`abnormalities and gene mutations are now integrated in clinical
`environments [11-17]. These considerable efforts contributed to the
`discovery and development of promising drugs for AML specifically
`targeting gene mutations, apoptotic pathways, and cell surface anti-
`gens. Novel liposomal formulations of classical cytotoxic agents are
`also promising. Midostaurin, gemtuzumab ozogamycin, glasdegib,
`
`venetoclax, ivosidenib, enasidenib,gilteritinib, CPX-351, and oral azac-
`itidine were approved by the Food and Drug Administration (FDA) of
`for AML patientsin less than 3 years between 2017 and 2020[18, 19]
`(Table 1).
`Rather than just another review stacking up one novel drug after
`another, this article will try to outline the perspectives for the com-
`ing years in the field of AML [20, 21]. Indeed, there are now numer-
`ous clinical research opportunities offered to clinicians with these
`new molecules and with those under development. With this sudden
`over-abundanceofchoices, wefeel like a lottery player who gets rich
`overnight and wonders whathe’s going to do withitall!
`
`2 | VENETOCLAX IN AML, THE MAGIC
`POTENTIATOR
`
`The anti-apoptotic BCL 2 (BCL-2) protein is overexpressed in AML,
`especially in leukemic stem cells that are supposed to be responsible
`for chemoresistance and relapse. BCL-2 overexpression is a poor
`risk factor in AML and is associated with chemoresistance [22].
`BCL-2 inhibition by small molecule inhibitors kills AML blasts, targets
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`WILEY
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`oxidative phosphorylation, and selectively eradicates leukemic stem
`cells [23, 24].
`In AML patients, contrary to chronic lymphocytic
`leukemia, venetoclax - an oral, selective, small-molecule inhibitor of
`
`comparable, and toxicity is likely to be lower with the doublet, although
`this important question should be the matter of prospective random-
`ized trials.
`
`Beyond the population of unfit patients, venetoclax is likely to
`become the drug of choice for combination therapy in virtually all
`AML patients. In relapse or refractory AML, the preliminary results
`of combinations with other small molecules inhibitors such as FLT3,
`
`IDH, or MDM2 inhibitors seem very promising [37, 38]. In patientsfit
`for intensive chemotherapy, adding venetoclax to 7+3 is feasible and
`induces promising responserates, especially in patients with interme-
`diate cytogenetic risk or with NPM1 or IDH mutations [25]. In these fit
`patients who have achieved CR after intensive induction chemother-
`apy, venetoclax in combination with intermediate dose cytarabine as
`consolidation therapy and/or with azacitidine as maintenance therapy
`so as to eradicate residual disease will be an important scope of inves-
`tigation. To date, 91 clinical trials with venetoclax in AML are recorded
`on theclinicaltrials.gov Website, thus highlighting the tremendous
`interest for this drug in AML. This has been confirmed at the virtual
`2020 American Society of Hematology meeting where noless than 10
`oral communications dealt with venetoclax based-combinations. Vene-
`
`toclax is becoming the drug of choice to combinewithall kind of ther-
`apeutic strategies in AML including high or low intensity chemother-
`apy, novel agents, and tyrosine kinase inhibitors. In a phase 2 trial, a
`low-intensity backboneof cladribine/low dose cytarabine plus veneto-
`clax alternating with azacitidine plus venetoclax for older patients with
`AML,yielded very high rates of durable MRD negative CR (96% CR/CRi
`and 80% MRD negative). With a median follow-up of 11+ months, the
`median OS wasnotreached, with 6- and 12-month OSrates of 86%
`
`and 70%, respectively [39]. Venetoclax has been also combined with
`intensive chemotherapyincluding CPX-351 or FLAG-Ida regimen [40,
`41]. These combinationsare feasible provided that the dose and dura-
`tion of venetoclax exposure is reduced. Prolonged myelosuppression
`and infections remain a major problem with this type of combinations
`which will be reserved for suitable patients. In FLT3 mutated AML,
`combining venetoclax plus FLT3 inhibitors such as quizartinib orgilter-
`itinib with or without hypomethylating agents also induced impressive
`responserates in R/R AML patients [42, 43]. However, AML patients
`with TP53 mutations did not appear to benefit from venetoclax based-
`treatment. Indeed, the combination of venetoclax and decitabine was
`
`associated with inferior response rate, shorter response duration,
`higher MRDpositivity, and a poor median OSof 5.2 months[44].
`
`BCL-2 - is not very active as a single agent with perhaps, the excep-
`tion of NPM1 or IDH mutation subgroups [25, 26]. However, when
`combined to low-dose cytarabine or with hypomethylating agents,
`venetoclax dramatically increases the CR rates, thus demonstrating
`synergistic activity in patients. Venetoclax has been recently approved
`in combination with hypomethylating agents asfirst line therapy in
`AML patients whoareineligible to receive standard induction therapy
`on the basis of high response rates and promising response durations
`in a Phase 1b/2 trial [27, 28]. These results have been very recently
`confirmed in the randomized, placebo-controlled, VIALE-A Phase 3
`trial which demonstrated the superiority of azacitidine plus venetoclax
`over azacitidine plus placebo in terms of CR rate (66.4% vs. 28.3%),
`duration of response (17.5 vs. 13.4 months), and OS (14.7 vs. 9.6
`months) [29]. These differences are highly statistically and clinically
`significant. This major breakthrough is reminiscent of the one made
`more than 40 years ago whenanthracyclines were added to cytarabine
`in patients eligible for intensive chemotherapy. Furthermore, the
`CR rate with azacitidine-venetoclax is >70% in the subgroups with
`IDH1 or IDH2 mutations [30]. These unprecedented results compared
`favorably with intensive chemotherapyin fit patients and generate
`hope for a cure in some patients. With the exception of the risk of
`tumorlysis syndrome and increased incidence of febrile neutropenia,
`no unexpected adverse event emerged, thus ensuring the widespread
`use of this combinationin this difficult-to-treat population of unfit or
`elderly patients. Venetoclax combined with low-dose cytarabine was
`also superior to low-dose cytarabine in the VIALE-C Phase3 trial [31].
`Thus, doublet azacitidine-venetoclax is becoming the new standard
`of care in patients ineligible for intensive induction chemotherapy and
`the standard arm to overcomein clinical trials. Planned or on-going
`clinical trials are already comparing this doubletto triplets with small
`molecule inhibitors or monoclonal antibodies. For example, the first
`results of the azacitidine-venetoclax-ivosidenib triplet may reach a
`100% rate of CR in treatment-naive AML patients with |DH1 mutations
`(EHALibrary. DiNardo C. 06/12/20; 294963; $143).
`There is an on-going debate on howto define patients unfit for
`intensive induction chemotherapy [32-34]. There are no absolute
`clear-cut criteria to unambiguously select the patients, and certain
`parameters used in the majority studies, such as performancestatus(a
`highly subjective criterion) or age, are questionable in this setting [34].
`It has been suggesting that comorbidity, physical capacities, and nutri-
`tional status may be more relevant than performancestatus or age [35].
`What about a 70-year-old patient with a normal karyotype, an ECOG
`performancestatus of 2 and no comorbidity? In routine, this patientis
`fit for chemotherapy especially when novaluable alternative is avail-
`able [36]. However, patients of the VIALE-A study could be included in
`the trial on the sole basis of the ECOGcriteria of 2; thereforeitis likely
`onco-hematology laboratories increase their turnaround in order to
`
`that this Phase3trial has included asubstantial numberof patients that allow clinicians to prescribe these agents in a timely manner. It has long
`were otherwisefit for chemotherapy outside clinical trials. Therefore,
`been postulated that AML represents an oncologic emergency and
`many physicianswill be tempted to replace intensive chemotherapy by
`should be treated withoutdelay, especially in younger patients treated
`azacitidine-venetoclax in older patients since CR rate and survival are
`by intensive chemotherapy [45]. However, recent studies have proven
`
`IDH AND FLT3 INHIBITORS, THE SMART
`3 |
`DRUGS WITH COMPANION BIOMARKERS
`
`With the developmentand recent approval of drugs targeting specific
`mutations such as FLT3, IDH1, and IDH2, it has become critical that
`
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`RECHER
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`that waiting a short period of time so as to characterise molecular
`alterations and design tailored treatments at diagnosis is safe [46, 47].
`It is now crucial that clinicians be knowledgeable on a panel of gene
`mutationsincluding at least FLT3, |IDH1, |IDH2, NPM1, CEBPA, and TP53
`at the time of diagnosis (48-72 h) in order to guide initial treatment.
`Furthermore, since AML clones and subclones are subject to clonal
`evolution under the therapeutic pressure of either chemotherapy
`or targeted agents, repeating molecular testing in each phase of the
`disease (refractory or relapse) should be mandatory. Recent advances
`inthe treatment of AML with FLT3 or IDHinhibitorsillustrate well this
`
`recent development.
`
`3.1 |
`
`IDH1 inhibitors
`
`Somatic mutationsofisocitrate dehydrogenase 1 (IDH1®132) genes are
`found in 6%-10% of AML patients [48]. |IDH1 mutations are mostfre-
`quent in AML with normal karyotype and associated with NPM1 and
`DNMT3A mutationsat diagnosis [49]. Their prognostic impact mainly
`dependson the mutational context [50-52]. Furthermore, IDH1 muta-
`tions, which have been described in clonal hematopoiesis, are consid-
`ered as early event during leukemogenesis, stable at relapse and thus,
`have emerged as promising therapeutic targets. It is also noteworthy
`that the molecular landscape of AML with IDH1 mutations observed at
`R/R disease under chemotherapyselection pressure differs from diag-
`nosis with an increased frequency of SRSF2, ASXL1, RUNX1, NRAS, and
`TP53 co-occurring mutations [49, 53].
`lvosidenib - an oral, targeted, small-molecule inhibitor of mutant
`IDH1 - has been evaluated as a single agent in a Phase 11 study in
`relapsed or refractory (R/R) AML with IDH1 mutation [53]. The fre-
`quencyof Grade 3 or higher treatment-related adverse events was low,
`mainly a prolongation of the QT interval, leukocytosis, and differen-
`tiation syndrome which are manageable [54]. CR or CR with partial
`hematologic recovery (CRh) was 30.4% with 21.8% CR, whereas CRi
`was 11.7%. It should be noted that clonal or subclonal mIDH1 had sim-
`
`ilar CR/CRh rates. Furthermore, mutation clearance was observed in
`
`21% of responding patients, thus demonstrating that deep response
`may be achieved in somepatients. The median duration of response
`was 9.3 months in CR patients. The median OS was8.8 months. Based
`on these promising results, ivosidenib was recently approved by the
`FDA.
`The mechanisms of resistance to ivosidenib were studied in
`
`patients whofailed to or relapsed after the response to this drug
`[55]. Receptor tyrosine kinase pathway mutations and mutations
`in NRAS and PTPN11 were significantly associated with the lack
`of
`response to ivosidenib.
`Interestingly, emerging mutations in
`patients who relapsed or progressed under ivosidenib were IDH or
`non-IDH-related. Indeed, mutations of resistance in a second site of
`
`The preliminary results of ivosidenib combined with azacitidine
`whentreating naive patients showed a CR rate of 70% and may reduce
`the emergence of mutantresistant clones [56].
`
`3.2 |
`
`IDH2 inhibitors
`
`Somatic mutations of the IDH2 gene, either IDH28149 or IDH2R172,
`occur in 5%-15% and 1%-4% of AML, respectively [48]. Like IDH1,
`IDH2 mutations are frequently found in normal karyotype AML [57,
`58]. At diagnosis, IDH2R14° mutations are associated with NPM1 and
`DNMT3A mutations whereasin the relapse/refractory setting, muta-
`tions of the SRSF2, DNMT3A, RUNX1, ASXL1, NRAS, and BCOR genes
`emerge as the most frequent co-mutations [11, 48, 59]. IDH2172 muta-
`tions are associated with DNMT3A and BCOR mutations and mutually
`exclusive with NPM1 and otherclass-defining mutations [49]. There-
`fore, AML with IDH28172 has been recognized as a defined subgroup
`of the AML genomicclassification[11].
`Enasidenib - an oral, targeted, small-molecule inhibitor of mutant
`IDH2 - has been evaluated as a single agent in a Phase 1 study in
`mutant IDH2 R/RAML patients and subsequently approved by the FDA
`[60]. A low frequency of Grade 3 or higher treatment-related adverse
`events was reported, mainly leukocytosis and differentiation syndrome
`[59, 61]. The overall response rate was 40.3% including 19.3% CR and
`6.8% CRi. The median OS was 9.3 months and reached 19.7 monthsin
`
`CR patients. CRs were observedin patients with subclonal |DH2 muta-
`tions, and a variantallele frequency of IDH2 mutant, which measures
`the mutational burden, was not associated with the response. Also,
`whereasin some CRpatients, |DH2 mutation clearance wasachieved,
`IDH2 mutational burden did not decrease in all responding patients
`during treatment, possibly due to the maturation of leukemic blasts
`into the functional neutrophils carrying the mutation. The mechanisms
`of resistance may involve the emergence of second-site IDH2 muta-
`tions, IDH2-mutant subclones with neomorphic mutationsin IDH1, co-
`occurring mutations in NRAS, and other MAPK pathwayeffectors or
`complex clonal evolution [59, 62, 63].
`A recent randomized Phase 2 trial of azacitidine versus azacitidine
`
`plus enasidenib in newly diagnosed AML patients unfit for intensive
`chemotherapy showeda significantly higher CR rate with the combina-
`tion comparedto azacitidine alone (53% vs. 12%) and a median dura-
`tion of response of 24.1 months in the combination arm (EHALibrary.
`DiNardo C. 06/12/20; 294959; $139).
`Whereas IDH inhibitors in combination with azacitidine yielded
`somevery interesting response rates compared to azacitidine alone,
`one openissue will be to determine which induction regimen to choose
`between azacitidine-venetoclax and azacitidine-IDH inhibitors. Will it
`
`be more appropriate to start with the standard azacitidine-venetoclax
`and reserve the IDH inhibitors for relapse? Or will triplets eradicate
`IDH1 or the emergence of IDH2®44° clones were detected in ~25%
`the diseaseatfirst line? Which inhibitor will we use in patients with
`other concomitant targetable mutations, such as FLT3 or TP53? In
`of resistant patients, whereas potentially actionable mutations in
`fit patients, the addition of ivosidenib or enasidenib to intensive
`genes such as FLT3, NRAS, or KRAS were also identified, thus indi-
`
`cating that molecular rescreening is important at each stage of the chemotherapyis under evaluation in an international Phase3trial
`disease.
`involving several cooperative AML study groups (NCT03839771).
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`
`Several others IDH1 or IDH2 inhibitors including drugs that target
`both mutations are underinvestigation [64].
`
`3.3.
`
`|
`
`FLT3 inhibitors
`
`Mutations in the FLT3 gene are among the most common mutations
`in AML, occurring in up to 30% of patients [65]. There are twodis-
`tinct activating FLT3 mutations: internal tandem duplications (ITD)
`in the juxta-membrane domain and point mutations in the tyrosine
`kinase domain 2 (TKD). FLT3 mutations are associated with an aggres-
`sive disease course, especially FLT3-ITD which generally predicts an
`early relapse and poor prognosis. Through clonal selection under
`chemotherapy,a higher mutantallelic burdenis frequently observed at
`relapse, thus indicating that AML cells have become more addicted to
`FLT3 signalling. This is an important point because at least in preclin-
`ical settings, FLT3-mutantallelic burden andclinical status(i.e., diag-
`nosis versus relapse samples) are predictive of the response to FLT3
`inhibitors in AML [66].
`Midostaurin - a staurosporine analog with a multikinase inhibitory
`activity against KIT, PDGFR, PKC, VEGF, and FLT3 (amongst others)
`- wasthefirst FLT3 inhibitor to be approved for frontline therapy in
`AML patients with FLT3 mutationsandfit for intensive chemotherapy
`[67]. In the randomized Phase 3 trial RATIFY, midostaurin and placebo
`were added to standard “7+3”induction chemotherapy and high-dose
`cytarabine consolidation followed by a 12-monthssingle agent main-
`tenance in younger patients (18-60 years) with FLT3-ITD or FLT3-
`TKD mutations. The CR rates were similar in both groups. However,
`midostaurin significantly improved the 4-year overall OS from 44.3%
`to 51.4%, compared with placebo [7]. The benefit of midostaurin was
`observed in FLT3-ITD patients, whatever theallelic ratio, and in FLT3-
`TKDpatients. A subsequent exploratory analysis based on the FLT3-
`ITD patient of the RATIFY trial showed that the impact of midostau-
`rin wassignificant in the three prognostic subgroups of the ELN2017
`classification which includes NPM1, RUNX1, ASXL1, and TP53 as well
`
`as cytogenetic risk [68]. Furthermore, the benefit of midostaurin was
`independentfrom the allogeneic stem cell transplantation. A Phase 2
`study suggested that older patients aged 60-70 years mayalso benefit
`from midostaurin [69]. Midostaurin was approvedin Europefor induc-
`tion, consolidation, and maintenance, whereas it was only approved
`for induction and consolidation in the US indicating that the need
`for midostaurin as maintenanceis uncertain. However, this postulate
`could also apply to the consolidation phase since RATIFY was not
`designed to demonstrate that midostaurin treatment beyond induction
`chemotherapywasessential. Anyhow,since this approval and because
`FLT3 mutated patients present with a high tumor burdenat diagnosis,
`the results of FLT3 mutational screen must been foundrapidly.
`Two randomized Phase 3 trials with second generation FLT3
`inhibitors were recently conducted in R/R AML patients with FLT3
`mutations(gilteritinib) or FLT3-ITD only mutations (quizartinib) [70,
`71]. In both studies, the FLT3 inhibitor as a single agent was superior
`to the standard of care with high or low intensity chemotherapyin
`terms of response and OS. However, while gilteritinib has been broadly
`
`WILEY+
`
`approved in North America, Europe and Japan, quizartinib was only
`registered in Japan.
`Gilteritinib is an oral, small molecule inhibitor, highly selective of
`FLT3 acting against both FLT3-ITD and FLT3-TKD mutations and only
`acting marginally against cKIT [72, 73] which distinguishes it from
`quizartinib andlikely explains the weak myelosuppression observed in
`patients. Gilteritinib also targets AXL, another tyrosine kinase impli-
`cated in the resistance to chemotherapy and FLT3inhibitors [74, 75].
`In the pivotal Phase 3 ADMIRAL study, AML patients with R/R FLT3-
`mutated AML were randomized between 120-mg/daygilteritinib and a
`standard of care with high or low intensity regimen defined by physi-
`cians prior to randomization [70]. It is important to keep in mind that
`few patients of the ADMIRALtrial had previously been exposed to
`midostaurin, which is no longer the case. Gilteritinib induced higher
`CR/CRh and CR rates (34.0% vs. 15.3% and 21.1% vs. 10.5%, respec-
`tively) and significantly improved OS (median OS, 9.3 vs. 5.6 months).
`Adverse events were more frequent in the standard chemotherapy
`arm, with the exception ofliver transaminase elevations. QTc prolon-
`gation, differentiation syndrome, and lipase elevation are very rare
`events in the context of gilteritinib treatment (<5%), whereas pos-
`terior reversible encephalopathy syndromes have been exceptionally
`reported [54, 76]. Off-target activating mutations in genes of the
`RAS/MAPKpathway have been identified as a key mechanism of the
`resistance to gilteritinib and confirmed in patients of the ADMIRAL
`trial who relapsed ongilteritinib treatment in whom in-target FLT3-
`F691L mutations werealso detected [77, 78].
`Phase 3 randomizedtrials comparingfirst line intensive chemother-
`apy plus midostaurin or second generation inhibitors are ongoing,
`and many combinations with hypomethylating agents or targeted
`agents are also being investigated [79]. Furthermore, other novel FLT3
`inhibitors are under development, andit is foreseeable that clinicians
`may have a handful of FLT3 inhibitors in order to deal with clonal evo-
`lution, drug-drug interactions, adverse events, or co-morbid conditions
`just like BCR-ABL inhibitors for Philadelphia-chromosome-positive
`leukemia [80-83].
`Patients with FLT3-ITD mutations are generally candidatesto allo-
`geneic stem cell transplantation, even though the post-transplant
`relapse rate remains a problem [84, 85]. Interestingly, sorafenib - a
`multikinase inhibitor with potent activity against FLT3 - has demon-
`strated clinical activity in FLT3-ITD patients having relapsed after
`transplantation [86]. A subsequent comprehensive preclinical study
`elegantly demonstrated that sorafenib,
`like other FLT3 inhibitors,
`increased the IL-15 production by FLT3-ITD leukemic cells leading to
`the potentiation of the allogeneic CD8+ T cell response as well as
`disease eradication in preclinical models [87]. As a clinical translation
`of this finding, the randomized Phase 3 SORMAIN trial demonstrated
`that sorafenib maintenance therapy reducestherisk of relapse and
`death after transplantation in AML patients with FLT3-ITD mutations
`[88]. Reducing therisk of relapse after allogeneic stem cell transplanta-
`tion by maintenance therapy with non-cytotoxic drugsis an activefield
`of research going beyond FLT3inhibitors, and virtually all the small
`molecules inhibitors having shownefficacy in AML will be assessed in
`this context [89, 90].
`
`

`

`7| WILEY
`
`RECHER
`
`4 | TP53: WANTED, DEAD, OR ALIVE
`
`Although the TP53 tumor suppressor gene is the most frequently
`mutated gene in human cancer,its incidence in AML is relatively low
`(5%-20%) and increases with age or in therapy-related AML [48].
`Patients with TP53 mutations have one of the worst prognosis in AML
`because their disease is both chemo and immuneresistant, as shown
`
`by the poorresponserate to standard treatments including intensive
`chemotherapy and hypomethylating agents and the high rate of relapse
`after allogeneic stem cell transplantation [91-94]. Treatment of this
`AML subgroup is an urgent unmet medical need, and therefore, huge
`efforts have been made to drug the undruggable. Thefirst glimmer of
`hope came from eprenetapopt (APR-246), which is the first-in-class
`small molecule that selectively targets TP53 mutated cancercells [95,
`96]. Furthermore, eprenetapoptacts in synergy with azacitidine [97].
`In two recent phase2 trials designed for TP53 mutated myelodysplas-
`tic syndrome or AML, eprenetapopt combined with azacitidine induced
`an overall response rate of 62%-71% (44%-47% CR) with a median
`duration of response at 8-10.4 months. [98, 99]. Neurologic toxicity
`emerged as the main adverseeffect with this drug. Furthermore, it has
`been recently shown that AML with TP53 mutations are associated
`with an infiltration of cytotoxic lymphocytes in the tumor microenvi-
`ronment, indicating that immune intervention could be of valuein this
`subgroup of patients [100, 101]. Altogether and even though these
`data are immature, there is reasonable hope to improve the outcome
`of patients with TP53 mutated-AML in the near future.
`
`5
`
`| CHEMOTHERAPY’S NOT DEAD(YET)
`
`A sizable proportion of intermediate and good-risk AML patients are
`cured by intensive chemotherapyin one shot(i.e., without the need
`for allogeneic stem cell transplantation and withoutrelapse). For these
`patients who generally receive one 7 + 3 induction cycle then three
`cycles of intermediate-to-high dose cytarabine, treatmentis definitely
`completed in 6 months, and thereafter, the patients are treatment-
`free for the rest of their life. In these patients, the added value of new
`drugswill be challenging to demonstrate both in termsof efficacy and
`duration of treatment because most new drugs have been developed
`so as to be administered on a long-term basis. However, well-known
`adverse eventsincluding profound myelosuppression,gastro-intestinal
`toxicity, severe mucositis, and infections as well as the strong impact
`of chemotherapyon quality oflife remain of concern. CPX-351,a dual-
`drugliposomal combination of daunorubicin and cytarabine with a syn-
`ergistic drug ratio, was approvedfor the treatmentof adults with newly
`diagnosed therapy-related AML or AML with myelodysplasia-related
`changes[102]. Long-term results of the pivotal phase 3 trial shown at
`ASH 2020 confirmed the superiority of CPX-351 over standard “3+7”
`chemotherapy and the particular good outcomeof patients who were
`allografted in first response after CPX-351 [103]. Interestingly, CPX-
`351 accumulates in the bone marrow where it has been shown to
`
`be taken up to a greater extent by AML cells than normal bone mar-
`row cells and sparing normal tissues [104]. In a clinical context, this
`
`translates into improvedefficacy (a higher responserate) but also into
`increased tolerability to induction chemotherapy. Nurses were proba-
`bly amongthefirst to notice this curious effect of CPX-351 compared
`to free daunorubicin and cytarabine: much less mucositis, gastroin-
`testinal (Gl) toxicity, and nohairloss.It is generally recognized by care-
`givers that CPX-351 is better tolerated than the standard 7 + 3, even
`though the Phase3 trial did not clearly demonstratethis point. Further-
`more, when ranking adverse events, it is noteworthy that hair-loss is
`the most commonside effect reported as severe by the patients, while
`caregivers are more proneto declareinfections, suggesting that quality
`of life with CPX-351 should be better than with 7+3 [105]. Therefore,
`it is tempting to foresee that CPX-351 indications could extend beyond
`the label to be broadly applied in de novo AML.In this regard, the results
`of the ongoing Phase 3 trial of the German AMLSGstudy group, cur-
`rently assessing CPX-351 versus standard “7+3” in newly diagnosed
`AML andintermediate- or adverse genetics (>18 y) (NCT03897127),
`will be of great importance for AML patientsfit for chemotherapy.
`
`6 | REVISITING THE CONCEPT OF REMISSION
`MAINTENANCE WITH ORAL THERAPY IN AML
`
`Preventing relapse after induction and consolidation therapy in
`AML has long been a major challenge especially in older patients
`ineligible for allogeneic stem cell
`transplantation [106]. While
`there have been some interesting data with drugs such as the
`histamine dihydroc